Many tumors (especially B-cell lymphomas) associated with AIDS and immunosuppression are infected by EBV in a latent form. There are no established antiviral therapies that target latent EBV, so treatment relies upon conventional cytotoxic and immune-reconstituting therapies, which often fail. However, it is known that transcriptional activation of either EBV immediate-early gene (BZLFl or BRLFl) results in the switch to the cytolytic form of EBV infection. In the cytolytic type of EBV infection, virally encoded kinases are expressed that phosphorylate the prodrug ganciclovir (GCV) into its toxic form. We have recently shown that both irradiation (XRT) and certain chemotherapeutic agents can induce cytolytic EBV. We hypothesize that intentional activation of cytolytic viral genes in EBV-positive malignancies can allow tumor-specific targeting for clinical effect. We have three specific aims. First, to perform a phase I study examining whether XRT induces lytic EBV in AIDS-related CNS lymphomas (which are 100% EBV-positive), and whether GCV can enhance therapy when combined with XRT. Similarly, in aim 2, we will use clinical samples from different EBV-positive tumors before and following XRT or chemotherapy to characterize and model the induction of the EBV lytic cascade in human tumors in vivo. Third, we have developed novel methodologies for targeted gene delivery of BZLF1 to EBV-positive tumors and will investigate their use in vitro/in vivo for inducing lytic EBV expression.